Functional analysis of Tgfbm3 locus in vascular development and disease

描述（申请人提供）：转化生长因子b1 （TGFbl）信号通路在临床上非常重要。它直接涉及几种出生缺陷，包括马凡综合征、遗传性出血性毛细血管扩张症（HHT）、Camurati-Engelmann病和腭裂，以及影响人类的两种最重要的多因素疾病，即癌症和心血管（CV）疾病的病因。TGFbl也是免疫调节的关键调节因子。编码TGFbl信号通路组分的基因（包括TGFB1）已被证明在人类中具有功能多态性，并且已发现特定TGFB1多态性变异的携带者与癌症、动脉粥样硬化、心肌梗死（Ml）、高血压和其他心血管疾病的疾病易感性之间存在遗传关联。本研究的目的是鉴定和表征影响体内TGFbl活性的遗传变异的不同功能，特别是在血管生成和心血管疾病方面。本提案的具体目的是表征小鼠12号染色体上TgfbmS位点遗传修饰的变异，并确定它们在血管生物学中的作用，以及2p25.1的同源基因在人类Ml风险中的作用。这一信息：a)将增加我们对TGFB1介导的血管重构的分子途径的理解，b)可能为评估已知与TGFB1相关的疾病的疾病风险提供筛选工具，将为此类疾病的预防性药物开发提供靶标，d)可能为抗tgfb药物治疗的反应提供预测标记

DESCRIPTION (provided by applicant): The transforming growth factor b1 (TGFbl) signaling pathway is clinically very important. It is directly implicated in several birth defects, including Marfan Syndrome, Hereditary Hemorrhagic Telangiectasia (HHT), Camurati-Engelmann disease and cleft palate, as well as being involved in the etiology of the two most important multifactorial diseases affecting humans, namely cancer and cardiovascular (CV) disease. TGFbl is also a key regulator of immunomodulation. Genes encoding components of the TGFbl signaling pathway including TGFB1 have been shown to be functionally polymorphic in humans, and genetic associations have been found between carriers of specific TGFB1 polymorphic variants and disease susceptibility for cancer, atherosclerosis, myocardial infarction (Ml), hypertension and other cardiovascular diseases. The goal of this research is to identify and characterize the differential functions of genetic variants that influence the activity of TGFbl action in vivo, particularly with respect to angiogenesis and CV disease. The specific objective of this proposal is to characterize variants responsible for genetic modification within the TgfbmS locus on mouse chromosome 12 and to determine their role in vascular biology, and the role of orthologous genes at 2p25.1 in risk for Ml in humans. This information:a)Will increase our understanding of molecular pathways involved in TGFbl-mediated vascular remodeling, b) May provide screening tools for assessment of disease risk in ailments known to have a TGFB1 associationc) Will provide targets for prophylactic drug development of such diseases d) May provide predictive markers for response to anti-TGFb drug therapies